This project will test predictions based on the theory that in susceptible individuals subtle differences in the immune response to certain infectious agents are associated with etiology and pathogenesis of rheumatoid arthritis (RA). The focus of this project will be on analyzing the role of antibodies (Abs) associated with RA. We will determine if there are quantitative or qualitative differences in the selection of VH genes used by susceptible versus resistant individuals in Ab responses generally and in the Ab responses to some of the agents suspected of triggering RA. The specific aims are: 1. Identify VH haplotypes in humans, using a set of precise V gene markers we have recently developed. 2. Compare VH haplotypes in rheumatoid arthritis patients and HLA-matched controls. 3. Compare VH gene utilization in RA patients and controls in polyclonal activation models. 4. Compare VH gene selection in specific Ab responses in RA patients and controls. Synthetic oligonucleotide probes will be employed to characterize individually both germline and expressed VH elements. The studies will include a definitive test of a possible genetic association between RA and the immunoglobulin VH locus, and analysis of the VH genes used to generate the expressed Ab repertoire, and an analysis of the VH genes used to make Abs to specific antigens in the context of genetic background. It is anticipated that the results will provide insights into molecular features of the immune system which permit development of RA and other autoimmune disorders.